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Vein graft adaptation and fistula maturation in the arterial environment

  • Author Footnotes
    1 These authors contributed equally to this work.
    Daniel Y. Lu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Elizabeth Y. Chen
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Daniel J. Wong
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Kota Yamamoto
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    VA Connecticut Healthcare System, West Haven, Connecticut
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  • Clinton D. Protack
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Willis T. Williams
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Roland Assi
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Michael R. Hall
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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  • Nirvana Sadaghianloo
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    Department of Vascular Surgery, University Hospital of Nice, Nice, France
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  • Alan Dardik
    Correspondence
    Corresponding author. Yale University School of Medicine, Vascular Biology and Therapeutics Program, 10 Amistad Street, Room 437, PO Box 208089, New Haven, CT 06520-8089. Tel.: +203 737 2082; fax +203 737 2290.
    Affiliations
    Yale University Vascular Biology and Therapeutics Program, New Haven, Connecticut

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

    VA Connecticut Healthcare System, West Haven, Connecticut
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  • Author Footnotes
    1 These authors contributed equally to this work.
Published:January 31, 2014DOI:https://doi.org/10.1016/j.jss.2014.01.042

      Abstract

      Veins are exposed to the arterial environment during two common surgical procedures, creation of vein grafts and arteriovenous fistulae (AVF). In both cases, veins adapt to the arterial environment that is characterized by different hemodynamic conditions and increased oxygen tension compared with the venous environment. Successful venous adaptation to the arterial environment is critical for long-term success of the vein graft or AVF and, in both cases, is generally characterized by venous dilation and wall thickening. However, AVF are exposed to a high flow, high shear stress, low-pressure arterial environment and adapt mainly via outward dilation with less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high-pressure arterial environment and adapt mainly via increased wall thickening with less outward dilation. We review the data that describe these differences, as well as the underlying molecular mechanisms that mediate these processes. Despite extensive research, there are few differences in the molecular pathways that regulate cell proliferation and migration or matrix synthesis, secretion, or degradation currently identified between vein graft adaptation and AVF maturation that account for the different types of venous adaptation to arterial environments.

      Keywords

      1. Introduction

      Vascular surgeons expose veins to the arterial environment during two common procedures, creation of vein grafts and arteriovenous fistulae (AVF). Adaptation of veins to the arterial environment, including the different hemodynamic conditions and increased oxygen tension, is characterized by venous wall dilation and thickening as an integration of the underlying processes of cellular migration and proliferation, as well as extracellular matrix deposition and remodeling. Successful venous adaptation is critical for long-term success of the vein graft or AVF, whereas unsuccessful adaptation, either insufficient or exuberant, may be a source of conduit failure that leads to patient morbidity and even mortality. Although our understanding of venous adaptation has substantially increased, this knowledge has not translated into successful therapy, and, accordingly, the failure rates of both vein grafts and AVF remain high, resulting in both patient suffering and significant health care expenditure [
      • Dember L.M.
      • Beck G.J.
      • Allon M.
      • et al.
      Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.
      ,
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ].
      AVF are the current optimal and preferred conduit for vascular access for hemodialysis. Compared with arteriovenous grafts and central venous catheters, AVF have the longest patency with fewest complications [
      • Gibson K.D.
      • Gillen D.L.
      • Caps M.T.
      • Kohler T.R.
      • Sherrard D.J.
      • Stehman-Breen C.O.
      Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.
      ,
      • Schwab S.J.
      • Harrington J.T.
      • Singh A.
      • et al.
      Vascular access for hemodialysis.
      ,
      • Asif A.
      • Roy-Chaudhury P.
      • Beathard G.A.
      Early arteriovenous fistula failure: a logical proposal for when and how to intervene.
      ,
      • Ravani P.
      • Palmer S.C.
      • Oliver M.J.
      • et al.
      Associations between hemodialysis access type and clinical outcomes: a systematic review.
      ]. Despite their superiority among dialysis access choices, AVF still exhibit relatively high failure rates, as high as 60% failing to mature adequately to support hemodialysis in some reports [
      • Juncos J.P.
      • Grande J.P.
      • Kang L.
      • et al.
      MCP-1 contributes to arteriovenous fistula failure.
      ,
      • Vazquez M.A.
      Vascular access for dialysis: recent lessons and new insights.
      ], and primary patency rates of approximately 60%–65% within 1 y [
      • Rooijens P.P.
      • Tordoir J.H.
      • Stijnen T.
      • Burgmans J.P.
      • Smet de A.A.
      • Yo T.I.
      Radiocephalic wrist arteriovenous fistula for hemodialysis: meta-analysis indicates a high primary failure rate.
      ,
      • Roy-Chaudhury P.
      • Spergel L.M.
      • Besarab A.
      • Asif A.
      • Ravani P.
      Biology of arteriovenous fistula failure.
      ]. Similarly, vein grafts are the most commonly used and preferred vascular conduit for bypass surgery [
      • Bradbury A.W.
      • Adam D.J.
      • Bell J.
      • et al.
      Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy.
      ,
      • Anwar M.A.
      • Shalhoub J.
      • Lim C.S.
      • Gohel M.S.
      • Davies A.H.
      The effect of pressure-induced mechanical stretch on vascular wall differential gene expression.
      ]. Like AVF, vein grafts also mature after surgical placement, a step thought to be necessary for long-term patency [
      • Owens C.D.
      Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications.
      ]. Vein grafts also have a significant rate of complications and failure, with 1-y primary patency rates reported to be as low as 60% [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Conte M.S.
      • Bandyk D.F.
      • Clowes A.W.
      • et al.
      Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.
      ,
      • Conte M.S.
      • Owens C.D.
      • Belkin M.
      • et al.
      A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts.
      ,
      • Gasper W.J.
      • Owens C.D.
      • Kim J.M.
      • et al.
      Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass.
      ]. Coronary artery vein grafts have higher patency rates, with 1-y patency rates of approximately 75%–90%, and 5- to 10-y patency rates >75% that decrease to 50% at ≥15 y [
      • Zeff R.H.
      • Kongtahworn C.
      • Iannone L.A.
      • et al.
      Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up.
      ,
      • Fitzgibbon G.M.
      • Kafka H.P.
      • Leach A.J.
      • Keon W.J.
      • Hooper G.D.
      • Burton J.R.
      Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years.
      ,
      • Desai N.D.
      • Cohen E.A.
      • Naylor C.D.
      • Fremes S.E.
      Radial Artery Patency Study I. A randomized comparison of radial-artery and saphenous-vein coronary bypass grafts.
      ,
      • Hamby R.I.
      • Aintablian A.
      • Handler M.
      • et al.
      Aortocoronary saphenous vein bypass grafts. Long-term patency, morphology and blood flow in patients with patent grafts early after surgery.
      ]. The similarities and differences between AVF and vein grafts are summarized in Table 1.
      Table 1Basic characteristics of vein grafts compared with AVF.
      Vein graftAVF
      Preferred conduit?Yes (bypass)Yes (access)
      Maturation in the arterial environment Outward remodelingYesYes
       Wall thickeningYesYes
      1-y patency60%–80%50%–65%
      Typical patient environmentCardiovascular risk factorsUremia/renal disease
      RunoffHigh resistanceLow resistance
      FlowArterialSupra-arterial
      PressureHigh (arterial)Low
      BranchesLigatedPatent
      Vein left intactNo (reversed vein graft)

      Yes (in situ vein graft)
      Yes
      Surgical mobilizationExtensiveMinor (typical)

      Extensive (transposed)
      Conduit diameter after remodelingMediumLarge
      Disturbed postsurgeryUndisturbedFrequently cannulated
      The surgical formation of a vein graft or an AVF exposes the vein to the arterial environment of high blood flow and pressure that are typically considered injurious and that stimulate venous adaptation to the new environment [
      • Anwar M.A.
      • Shalhoub J.
      • Lim C.S.
      • Gohel M.S.
      • Davies A.H.
      The effect of pressure-induced mechanical stretch on vascular wall differential gene expression.
      ]. This review compares both physiological and molecular adaptation of veins (“venous remodeling”), as either vein grafts (“vein graft adaptation”) or AVF (“AVF maturation”), to this different environment, using literature specific to venous adaptation and not based on arterial data.

      2. Surgical procedure

      Several aspects of the surgical procedure are noteworthy and likely to affect venous remodeling. Vein grafts can be performed either in reversed, nonreversed, or in situ fashion, generally at the discretion of the surgeon. Reversed vein grafts create a flow environment in which the endothelial cells remain aligned to the direction of flow and the valves remain in their normal alignment, allowing antegrade flow with minimal resistance or disturbance. Nonreversed vein grafts are prepared similarly but require valve destruction, creating flow disturbance and even turbulence near the valve remnants; the endothelial cells remain aligned to the direction of flow but the flow direction is 180° reversed compared with the native venous flow. In situ vein grafts similarly require valve destruction and have reversed flow on the endothelial cells, but the veins are not removed from the native tissue bed, leaving the venous adventitia, as well as the vasa vasorum and nervous innervation, intact. Vein grafts, both reversed and nonreversed, require extensive handling and irrigation, resulting in spasm as well as endothelial damage and inflammation [
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Mitra A.K.
      • Gangahar D.M.
      • Agrawal D.K.
      Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia.
      ,
      • Osgood M.J.
      • Hocking K.M.
      • Voskresensky I.V.
      • et al.
      Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein.
      ]. During coronary artery bypass, veins may be exposed to the colder environment of the bypass flow circuit and cardioplegia.
      Similarly, AVF may be created directly or transposed from a deeper bed, although transposition in reversed configuration with valve destruction is distinctly less common. The AVF procedure is usually performed with less mobilization and surgical manipulation of the vein compared with vein grafts, resulting in AVF being performed more quickly and with less trauma, ischemia, and endothelial injury compared with vein grafts.
      The systemic environment created by the comorbid conditions of the patient is often quite different between vein grafts and AVF. Vein grafts are typically created in patients with cardiovascular disease that is similarly frequently present in patients needing AVF. However, patients with AVF have advanced renal disease and uremia that is not present in many patients requiring vein grafts. Uremia is an independent factor that predisposes the AVF to failure to mature [
      • Dixon B.S.
      Why don't fistulas mature?.
      ,
      • Kokubo T.
      • Ishikawa N.
      • Uchida H.
      • et al.
      CKD accelerates development of neointimal hyperplasia in arteriovenous fistulas.
      ,
      • Liang A.
      • Wang Y.
      • Han G.
      • Truong L.
      • Cheng J.
      Chronic kidney disease accelerates endothelial barrier dysfunction in a mouse model of an arteriovenous fistula.
      ,
      • Wali M.A.
      • Eid R.A.
      • Dewan M.
      • Al-Homrany M.A.
      Intimal changes in the cephalic vein of renal failure patients before arterio-venous fistula (AVF) construction.
      ]. AVF are also cannulated for dialysis multiple times a week, unlike vein grafts that reside in atraumatic environments.

      3. Flow and pressure

      The minimum blood flow for hemodialysis in the United States is generally 350–450 mL/min, and to prevent venous collapse, the flow rate should exceed this minimum rate by at least 100 mL/min [
      • Robbin M.L.
      • Chamberlain N.E.
      • Lockhart M.E.
      • et al.
      Hemodialysis arteriovenous fistula maturity: US evaluation.
      ]. High flow rates correlate with successful access maturation, with 84% of fistulae with flows >500 mL/min eventually being adequate for dialysis, whereas only 43% of fistulas with flows <500 mL/min becoming adequate [
      • Robbin M.L.
      • Chamberlain N.E.
      • Lockhart M.E.
      • et al.
      Hemodialysis arteriovenous fistula maturity: US evaluation.
      ]. The National Kidney Foundation Clinical Practice Guidelines recommend a flow rate of 400–500 mL/min as a minimal threshold for re-evaluation of a fistula [

      National Kidney Foundation. Clinical Practice Guidelines and Clinical Practice Recommendations, 2006 Updates.: Available from: http://www.kidney.org/professionals/kdoqi/guideline_uphd_pd_va/va_guide4.htm.

      ]. In Europe and Japan, however, hemodialysis is currently performed with lower flow rates but with longer sessions compared with those performed in the United States [
      • Gallieni M.
      • Saxena R.
      • Davidson I.
      Dialysis access in Europe and North America: are we on the same path?.
      ,
      • Saran R.
      • Bragg-Gresham J.L.
      • Levin N.W.
      • et al.
      Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.
      ]. For example, in Europe, a minimal flow rate of 300 mL/min is the threshold for re-evaluation [
      • Tordoir J.
      • Canaud B.
      • Haage P.
      • et al.
      EBPG on vascular access.
      ].
      The blood flow in the cephalic vein in healthy, nonhemodialysis patients is approximately 28 ± 14 mL/min [
      • Albayrak R.
      • Yuksel S.
      • Colbay M.
      • et al.
      Hemodynamic changes in the cephalic vein of patients with hemodialysis arteriovenous fistula.
      ]. Studies evaluating successful radial-cephalic AVF reveal normal flow rates averaging between 600 and1000 mL/min, with many individual AVF exposed to even higher peak flows, and this magnitude of flow increases substantially in the larger diameter brachial-cephalic AVF (Table 2). Dixon et al. [
      • Dixon B.S.
      • Novak L.
      • Fangman J.
      Hemodialysis vascular access survival: upper-arm native arteriovenous fistula.
      ] reported that 90% of forearm AVF have flow between 500 and 2000 mL/min, whereas 90% of upper arm AVF have flow between 500 and 3000 mL/min. Corpataux et al. reported that shear stress increases from 5–10 dyne/cm2 to 24.5 dyne/cm2 after 1 wk, which then normalizes to 10.4 dyne/cm2 >3 mo [
      • Asif A.
      • Roy-Chaudhury P.
      • Beathard G.A.
      Early arteriovenous fistula failure: a logical proposal for when and how to intervene.
      ,
      • Corpataux J.M.
      • Haesler E.
      • Silacci P.
      • Ris H.B.
      • Hayoz D.
      Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
      ]. The substantially increased magnitude of blood flow in the AVF, typically much higher compared with arterial flow, we call “supra-arterial” magnitudes of flow (Table 1). With these high magnitudes of flow in the AVF, the character of the flow may be disturbed, for example, nonlaminar and highly disordered, even turbulent [
      • Krishnamoorthy M.K.
      • Banerjee R.K.
      • Wang Y.
      • et al.
      Hemodynamic wall shear stress profiles influence the magnitude and pattern of stenosis in a pig AV fistula.
      ,
      • Ene-Iordache B.
      • Remuzzi A.
      Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: low and oscillating shear stress locates the sites of stenosis.
      ,
      • Manning E.
      • Skartsis N.
      • Orta A.M.
      • et al.
      A new arteriovenous fistula model to study the development of neointimal hyperplasia.
      ,
      • Ojha M.
      • Cobbold R.S.
      • Johnston K.W.
      Influence of angle on wall shear stress distribution for an end-to-side anastomosis.
      ].
      Table 2Studies measuring flow in human AVF and vein grafts.
      StudyMeasurementFlow (mean ± SD)
      Wong et al.
      • Wong V.
      • Ward R.
      • Taylor J.
      • Selvakumar S.
      • How T.V.
      • Bakran A.
      Factors associated with early failure of arteriovenous fistulae for haemodialysis access.
      AVF (radiocephalic)-cephalic vein125 ± 102 mL/min intraoperatively

      710 ± 318 mL/min at 12 wk
      Lin et al.
      • Lin S.L.
      • Chen H.S.
      • Huang C.H.
      • Yen T.S.
      Predicting the outcome of hemodialysis arteriovenous fistulae using duplex ultrasonography.
      AVF (radiocephalic)-cephalic vein825.6 ± 424.3 mL/min

      in successful fistulae at 2–3 wk
      Yerdel et al.
      • Yerdel M.A.
      • Kesenci M.
      • Yazicioglu K.M.
      • Doseyen Z.
      • Turkcapar A.G.
      • Anadol E.
      Effect of haemodynamic variables on surgically created arteriovenous fistula flow.
      AVF (radiocephalic and brachiocephalic)-cephalic vein58 ± 23 mL/min intraoperatively

      472 ± 315 mL/min at d 1

      861 ± 565 mL/min at d 7
      Lin et al.
      • Lin S.L.
      • Huang C.H.
      • Chen H.S.
      • Hsu W.A.
      • Yen C.J.
      • Yen T.S.
      Effects of age and diabetes on blood flow rate and primary outcome of newly created hemodialysis arteriovenous fistulas.
      AVF (radiocephalic)-cephalic vein750.4 ± 392.2 mL/min—younger

      634.2 ± 310.3 mL/min—elderly

      at >1 wk
      Robbin et al.
      • Robbin M.L.
      • Chamberlain N.E.
      • Lockhart M.E.
      • et al.
      Hemodialysis arteriovenous fistula maturity: US evaluation.
      AVF (upper arm and forearm)-draining veins780 ± 401 mL/min in successful fistulae within 4 mo
      Dixon et al.
      • Dixon B.S.
      • Novak L.
      • Fangman J.
      Hemodialysis vascular access survival: upper-arm native arteriovenous fistula.
      AVF (brachiocephalic and radiocephalic)Brachiocephalic: 1247 mL/min

      Radiocephalic: 938 mL/min
      Albayrak et al.
      • Albayrak R.
      • Yuksel S.
      • Colbay M.
      • et al.
      Hemodynamic changes in the cephalic vein of patients with hemodialysis arteriovenous fistula.
      AVF (radiocephalic and brachiocephalic)-cephalic veinBrachiocephalic: 1983 ± 1199 mL/min

      Radiocephalic: 870 ± 322 mL/min
      Saucy et al.
      • Saucy F.
      • Haesler E.
      • Haller C.
      • Deglise S.
      • Teta D.
      • Corpataux J.M.
      Is intra-operative blood flow predictive for early failure of radiocephalic arteriovenous fistula?.
      AVF (radiocephalic)-pre-anastomotic radial artery minus post-anastomotic radial artery flow230 ± 194 mL/min intraoperatively

      753 ± 269 mL/min at 1 wk

      915 ± 393 mL/min at 1 mo

      in successful radiocephalic fistulae
      Fillinger et al.
      • Fillinger M.F.
      • Cronenwett J.L.
      • Besso S.
      • Walsh D.B.
      • Zwolak R.M.
      Vein adaptation to the hemodynamic environment of infrainguinal grafts.
      VG (infrainguinal bypasses)-greater saphenous vein104–206 mL/min at 1 wk

      57–82 mL/min at 1 y
      Owens et al.
      • Owens C.D.
      • Wake N.
      • Jacot J.G.
      • et al.
      Early biomechanical changes in lower extremity vein grafts—distinct temporal phases of remodeling and wall stiffness.
      VG (lower-extremity bypass)-greater saphenous, cephalic, or basilic vein161 ± 21.7 mL/min intraoperatively

      302.2 ± 47 mL/min (mean ± SEM) at 6 mo
      Owens et al.
      • Owens C.D.
      • Wake N.
      • Conte M.S.
      • Gerhard-Herman M.
      • Beckman J.A.
      In vivo human lower extremity saphenous vein bypass grafts manifest flow mediated vasodilation.
      VG (femoral-popliteal)-greater saphenous vein348.0 ± 153.2 mL/min (average age of graft: 1195.6 d)
      Greenfield et al.
      • Greenfield Jr., J.C.
      • Rembert J.C.
      • Young Jr., W.G.
      • Oldham Jr., H.N.
      • Alexander J.A.
      • Sabiston Jr., D.C.
      Studies of blood flow in aorta-to-coronary venous bypass grafts in man.
      VG (coronary artery bypass)-saphenous vein35 ± 2 mL/min (mean ± SEM) at 30 min after bypass
      Hamby et al.
      • Hamby R.I.
      • Aintablian A.
      • Handler M.
      • et al.
      Aortocoronary saphenous vein bypass grafts. Long-term patency, morphology and blood flow in patients with patent grafts early after surgery.
      VG (coronary artery bypass)-saphenous veinEarly (8–12 d postoperatively):

      To LAD: 79 ± 39 mL/min

      To Right Circumflex: 65 ± 17 mL/min

      To Left Circumflex: 68 ± 25 mL/min

      Late (average 2.5 y): To LAD: 67 ± 31 mL/min

      To Right Circumflex: 42 ± 17 mL/min

      To Left Circumflex: 60 ± 24 mL/min
      Gurné et al.
      • Gurne O.
      • Chenu P.
      • Buche M.
      • et al.
      Adaptive mechanisms of arterial and venous coronary bypass grafts to an increase in flow demand.
      VG (coronary artery bypass)-saphenous veinEarly: 56 ± 19 mL/min (average 9 d)

      Late: 50 ± 16 mL/min (average 23 mo)
      Walpoth et al.
      • Walpoth B.H.
      • Schmid M.
      • Schwab A.
      • et al.
      Vascular adaptation of the internal thoracic artery graft early and late after bypass surgery.
      VG (coronary artery bypass)-greater saphenous vein58 ± 29 mL/min intraoperatively

      50 ± 27 mL/min at 3 mo

      46 ± 27 mL/min at 10 mo
      LAD = left anterior descending artery; SD = standard deviation; SEM = standard error of the mean.
      The blood flow within vein grafts varies depending on several variables, including type of procedure, length and diameter of conduit, and the amount of resistance in the runoff bed distal to the vein graft. Accordingly, average flow rates for lower extremity bypasses typically vary from <100 to >300 mL/min, whereas average flow rates for coronary artery bypass are often <100 mL/min (Table 2). Flow rates over time are extremely difficult to assess, as the presence of a failing graft, even subclinically, as well as advancing proximal and/or distal disease, are significant confounding variables that usually precipitate intervention. Nevertheless, most studies show that vein grafts are exposed to flows of the arterial circulation that are typically much lower magnitude than to which AVF are exposed.
      In lower extremity vein grafts, average intraoperative shear stress was measured to be 23–27 dyne/cm2, which decreases by 1 y to 12 dyne/cm2 [
      • Gasper W.J.
      • Owens C.D.
      • Kim J.M.
      • et al.
      Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass.
      ,
      • Owens C.D.
      • Wake N.
      • Jacot J.G.
      • et al.
      Early biomechanical changes in lower extremity vein grafts—distinct temporal phases of remodeling and wall stiffness.
      ,
      • Owens C.D.
      • Rybicki F.J.
      • Wake N.
      • et al.
      Early remodeling of lower extremity vein grafts: inflammation influences biomechanical adaptation.
      ]. Fillinger et al. [
      • Fillinger M.F.
      • Cronenwett J.L.
      • Besso S.
      • Walsh D.B.
      • Zwolak R.M.
      Vein adaptation to the hemodynamic environment of infrainguinal grafts.
      ] showed that smaller diameter vein grafts are associated with much higher values of shear stress, with these values normalizing to 6–10 dyne/cm2 by 12 mo. Coronary vein grafts generally dilate little and have lower magnitudes of flow, with shear stress values reported to be ≤5 dyne/cm2 [
      • Shimizu T.
      • Ito S.
      • Kikuchi Y.
      • et al.
      Arterial conduit shear stress following bypass grafting for intermediate coronary artery stenosis: a comparative study with saphenous vein grafts.
      ,
      • Isobe N.
      • Kaneko T.
      • Taniguchi K.
      • Oshima S.
      Comparison of the rheologic parameters in left internal thoracic artery grafts with those in saphenous vein grafts.
      ].
      Fewer studies examine pressure, but pressure measurements in an AVF are generally significantly less than measurements in a vein graft [
      • Corpataux J.M.
      • Haesler E.
      • Silacci P.
      • Ris H.B.
      • Hayoz D.
      Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
      ,
      • Chan C.Y.
      • Chen Y.S.
      • Ma M.C.
      • Chen C.F.
      Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats.
      ]. Corpataux et al. [
      • Corpataux J.M.
      • Haesler E.
      • Silacci P.
      • Ris H.B.
      • Hayoz D.
      Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
      ] measured the cephalic vein pressure to be 49 ± 19/24.5 ± 6 mm Hg (systolic/diastolic) immediately after radial-cephalic AVF creation, and this did not increase 13 mo later. Animal studies are also generally consistent with this small increase in pressure [
      • Krishnamoorthy M.K.
      • Banerjee R.K.
      • Wang Y.
      • et al.
      Hemodynamic wall shear stress profiles influence the magnitude and pattern of stenosis in a pig AV fistula.
      ,
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ]. Vein grafts are typically exposed to arterial pressure [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • Chan C.Y.
      • Chen Y.S.
      • Ma M.C.
      • Chen C.F.
      Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats.
      ]. In toto, extensive examination shows that vein grafts are exposed to arterial magnitudes of pressure and flow, whereas AVF are exposed to supra-arterial magnitudes of flow at pressures typically much lower than arterial systolic pressure (Table 1).

      4. Outward remodeling

      Adaptation of the vein to the increased flow and shear stress of the arterial environment requires dilation by outward remodeling of the venous wall, described by Poiseuille's law, whereas increases in pressure and tensile stress require wall thickening, described by Laplace's law. These changes are thought to be mediated by the venous endothelium that senses hemodynamic forces and integrates these forces to allow successful adaptation without loss of luminal area and vessel patency [
      • Roy-Chaudhury P.
      • Spergel L.M.
      • Besarab A.
      • Asif A.
      • Ravani P.
      Biology of arteriovenous fistula failure.
      ,
      • Owens C.D.
      Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications.
      ,
      • Langille B.L.
      • O'Donnell F.
      Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent.
      ].
      Diameter expansion is thought to be a critical element of venous outward remodeling and predicts clinical success for both AVF and vein grafts [
      • Gasper W.J.
      • Owens C.D.
      • Kim J.M.
      • et al.
      Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass.
      ,
      • Feldman H.I.
      • Joffe M.
      • Rosas S.E.
      • Burns J.E.
      • Knauss J.
      • Brayman K.
      Predictors of successful arteriovenous fistula maturation.
      ,
      • Wong V.
      • Ward R.
      • Taylor J.
      • Selvakumar S.
      • How T.V.
      • Bakran A.
      Factors associated with early failure of arteriovenous fistulae for haemodialysis access.
      ,
      • Schanzer A.
      • Hevelone N.
      • Owens C.D.
      • et al.
      Technical factors affecting autogenous vein graft failure: observations from a large multicenter trial.
      ]. Although mediated by the endothelium, this process may require destruction of the internal elastic lamina to allow subsequent wall dilation [
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ,
      • Tomas J.J.
      • Stark V.E.
      • Kim J.L.
      • et al.
      Beta-galactosidase-tagged adventitial myofibroblasts tracked to the neointima in healing rat vein grafts.
      ]. Several studies examining venous dilation in AVF reported mean diameter increases from 2.3–3.2 to 5.8–6.6 mm, 3 mo after fistula creation. These values reflect a 45%–86% increase within the first month and an increase of up to 179% after 3 mo, correspond to an average cross-sectional area of approximately 10–12 mm2, and were associated with normalization of the shear stress [
      • Corpataux J.M.
      • Haesler E.
      • Silacci P.
      • Ris H.B.
      • Hayoz D.
      Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
      ,
      • Wong V.
      • Ward R.
      • Taylor J.
      • Selvakumar S.
      • How T.V.
      • Bakran A.
      Factors associated with early failure of arteriovenous fistulae for haemodialysis access.
      ,
      • Lin S.L.
      • Chen H.S.
      • Huang C.H.
      • Yen T.S.
      Predicting the outcome of hemodialysis arteriovenous fistulae using duplex ultrasonography.
      ,
      • Lin S.L.
      • Huang C.H.
      • Chen H.S.
      • Hsu W.A.
      • Yen C.J.
      • Yen T.S.
      Effects of age and diabetes on blood flow rate and primary outcome of newly created hemodialysis arteriovenous fistulas.
      ].
      Lower extremity vein grafts are associated with average dilation of approximately 20%–30% during the first few months after surgery, with minimal dilation afterward [
      • Gasper W.J.
      • Owens C.D.
      • Kim J.M.
      • et al.
      Thirty-day vein remodeling is predictive of midterm graft patency after lower extremity bypass.
      ,
      • Owens C.D.
      • Wake N.
      • Jacot J.G.
      • et al.
      Early biomechanical changes in lower extremity vein grafts—distinct temporal phases of remodeling and wall stiffness.
      ,
      • Owens C.D.
      • Rybicki F.J.
      • Wake N.
      • et al.
      Early remodeling of lower extremity vein grafts: inflammation influences biomechanical adaptation.
      ]. Fillinger et al. [
      • Fillinger M.F.
      • Cronenwett J.L.
      • Besso S.
      • Walsh D.B.
      • Zwolak R.M.
      Vein adaptation to the hemodynamic environment of infrainguinal grafts.
      ] reported that at 1 y postoperatively, initially smaller diameter vein grafts tended to dilate 20%–25%, whereas initially larger diameter vein grafts tended to constrict 10%–15%, achieving similar final diameters. Vein grafts in the coronary circulation may also show flow-mediated diameter remodeling, although they frequently exhibit a small amount of inward remodeling, consistent with their lower flow [
      • Nishioka T.
      • Luo H.
      • Berglund H.
      • et al.
      Absence of focal compensatory enlargement or constriction in diseased human coronary saphenous vein bypass grafts. An intravascular ultrasound study.
      ,
      • Lau G.T.
      • Ridley L.J.
      • Bannon P.G.
      • et al.
      Lumen loss in the first year in saphenous vein grafts is predominantly a result of negative remodeling of the whole vessel rather than a result of changes in wall thickness.
      ]. Thus, both vein grafts and AVF remodel their diameters, usually by dilation, depending on the magnitudes of flow in the new environment, normalizing the shear stress sensed by the venous endothelium.

      5. Wall thickening

      Wall thickening is the adaptation of the vessel wall to increased pressure; thickening has been studied extensively in several models of vascular injury and adaptation, especially in the arterial angioplasty and hypertension models. These models have shown that this process involves expansion of all the layers of the vessel via both extracellular matrix (ECM) deposition, as well as via cell proliferation and migration [
      • Owens C.D.
      Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications.
      ,
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Owens C.D.
      • Wake N.
      • Jacot J.G.
      • et al.
      Early biomechanical changes in lower extremity vein grafts—distinct temporal phases of remodeling and wall stiffness.
      ,
      • Owens C.D.
      • Ho K.J.
      • Conte M.S.
      Lower extremity vein graft failure: a translational approach.
      ]. Several types of cells are involved in wall thickening, including smooth muscle cells, adventitial fibroblasts, and bone marrow–derived progenitor cells. In addition to proliferation, smooth muscle cells may migrate from the medial to the intimal layer and differentiate from a contractile to synthetic phenotype; fibroblasts may similarly differentiate into myofibroblasts [
      • Roy-Chaudhury P.
      • Spergel L.M.
      • Besarab A.
      • Asif A.
      • Ravani P.
      Biology of arteriovenous fistula failure.
      ,
      • Owens C.D.
      Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications.
      ,
      • Mitra A.K.
      • Gangahar D.M.
      • Agrawal D.K.
      Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia.
      ,
      • Dixon B.S.
      Why don't fistulas mature?.
      ,
      • Tomas J.J.
      • Stark V.E.
      • Kim J.L.
      • et al.
      Beta-galactosidase-tagged adventitial myofibroblasts tracked to the neointima in healing rat vein grafts.
      ,
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Lee T.
      • Roy-Chaudhury P.
      Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.
      ,
      • Misra S.
      • Fu A.A.
      • Anderson J.L.
      • et al.
      The rat femoral arteriovenous fistula model: increased expression of matrix metalloproteinase-2 and -9 at the venous stenosis.
      ,
      • Roy-Chaudhury P.
      • Wang Y.
      • Krishnamoorthy M.
      • et al.
      Cellular phenotypes in human stenotic lesions from haemodialysis vascular access.
      ,
      • Shi Y.
      • O'Brien Jr., J.E.
      • Mannion J.D.
      • et al.
      Remodeling of autologous saphenous vein grafts. The role of perivascular myofibroblasts.
      ,
      • Kalra M.
      • Miller V.M.
      Early remodeling of saphenous vein grafts: proliferation, migration and apoptosis of adventitial and medial cells occur simultaneously with changes in graft diameter and blood flow.
      ,
      • Zhang W.D.
      • Bai H.Z.
      • Sawa Y.
      • et al.
      Association of smooth muscle cell phenotypic modulation with extracellular matrix alterations during neointima formation in rabbit vein grafts.
      ,
      • Borin T.F.
      • Miyakawa A.A.
      • Cardoso L.
      • de Figueiredo Borges L.
      • Goncalves G.A.
      • Krieger J.E.
      Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat.
      ,
      • Mima A.
      Hemodialysis vascular access dysfunction: molecular mechanisms and treatment.
      ]. Bone marrow–derived progenitor cells are capable of differentiation into both endothelial and smooth muscle cells within both AVF and vein grafts, although whether this occurs in humans is not clear [
      • Roy-Chaudhury P.
      • Wang Y.
      • Krishnamoorthy M.
      • et al.
      Cellular phenotypes in human stenotic lesions from haemodialysis vascular access.
      ,
      • Caplice N.M.
      • Wang S.
      • Tracz M.
      • et al.
      Neoangiogenesis and the presence of progenitor cells in the venous limb of an arteriovenous fistula in the rat.
      ,
      • Zhang L.
      • Freedman N.J.
      • Brian L.
      • Peppel K.
      Graft-extrinsic cells predominate in vein graft arterialization.
      ,
      • Xu Q.
      • Zhang Z.
      • Davison F.
      • Hu Y.
      Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice.
      ,
      • Diao Y.
      • Guthrie S.
      • Xia S.L.
      • et al.
      Long-term engraftment of bone marrow-derived cells in the intimal hyperplasia lesion of autologous vein grafts.
      ]. Neoangiogenesis also occurs during wall thickening, although its contribution to normal adaptation or maladaptive pathology is unclear [
      • Manning E.
      • Skartsis N.
      • Orta A.M.
      • et al.
      A new arteriovenous fistula model to study the development of neointimal hyperplasia.
      ,
      • Lee T.
      • Roy-Chaudhury P.
      Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.
      ,
      • Caplice N.M.
      • Wang S.
      • Tracz M.
      • et al.
      Neoangiogenesis and the presence of progenitor cells in the venous limb of an arteriovenous fistula in the rat.
      ,
      • Westerband A.
      • Crouse D.
      • Richter L.C.
      • et al.
      Vein adaptation to arterialization in an experimental model.
      ].
      Jacot et al. [
      • Jacot J.G.
      • Abdullah I.
      • Belkin M.
      • et al.
      Early adaptation of human lower extremity vein grafts: wall stiffness changes accompany geometric remodeling.
      ] reported increased wall thickness during human vein graft adaptation, from 0.47 ± 0.03 to 0.61 ± 0.004 mm, during the first 6 mo after implantation. Using intravascular ultrasound, Higuchi et al. [
      • Higuchi Y.
      • Hirayama A.
      • Shimizu M.
      • Sakakibara T.
      • Kodama K.
      Postoperative changes in angiographically normal saphenous vein coronary bypass grafts using intravascular ultrasound.
      ] reported similar wall thickening that accompanied outward remodeling in saphenous vein coronary artery bypass grafts. Similarly, Corpataux et al. [
      • Corpataux J.M.
      • Haesler E.
      • Silacci P.
      • Ris H.B.
      • Hayoz D.
      Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.
      ] reported increased wall cross-sectional area in AVF although the small increase in the AVF is likely due to the lower pressure in the AVF compared with the coronary vein graft.

      6. Venous remodeling integrates outward remodeling and wall thickening

      AVF are exposed to a high flow, high shear stress, low-pressure arterial environment and adapt mainly via outward dilation and less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high-pressure arterial environment and adapt mainly via increased wall thickening with less outward dilation (Fig. 1). Schwartz et al. [
      • Schwartz L.B.
      • O'Donohoe M.K.
      • Purut C.M.
      • Mikat E.M.
      • Hagen P.O.
      • McCann R.L.
      Myointimal thickening in experimental vein grafts is dependent on wall tension.
      ] confirmed this behavior using a rabbit model, showing that AVF are exposed to higher flow than vein grafts (AVF: 82 ± 17 mL/min; vein grafts: 16 ± 4 mL/min) as well as increased shear stress (AVF: 71 ± 50 dyne/cm2; VG: 0.96 ± 0.38 dyne/cm2) that was associated with increased dilation (AVF: 194%; VG: no change); vein grafts are exposed to higher pressure (VG: 62 ± 3 mmHg; AVF: 6 ± 2 mmHg) and had increased myointimal area (VG: 4.72 ± 0.83 mm2; AVF: 1.9 ± 0.55 mm2). Interestingly, Zilla et al. [
      • Zilla P.
      • Moodley L.
      • Scherman J.
      • et al.
      Remodeling leads to distinctly more intimal hyperplasia in coronary than in infrainguinal vein grafts.
      ] recently showed in a nonhuman primate model that vein grafts in the coronary circulation had lower mean velocity and shear stress, and lumen constriction and increased intimal thickening, compared with peripheral vein grafts that dilate.
      Figure thumbnail gr1
      Fig. 1Schema of vein graft adaptation and AVF maturation. AVF adapt largely through outward remodeling in response to supra-arterial flow, whereas vein grafts adapt largely through intimal/medial thickening in response to arterial pressure. + = positive; +++ = significantly positive.

      7. Molecular mechanisms of venous remodeling

      7.1 Vascular identity

      The developmental origin of vascular endothelial cells and smooth muscle cells is different, with Ephrin-B2 being a determinant of arteries and Eph-B4, a determinant of veins in the developing embryo; these determinants persist as markers of identity on adult vessels [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Kullander K.
      • Klein R.
      Mechanisms and functions of Eph and ephrin signalling.
      ,
      • Foo S.S.
      • Turner C.J.
      • Adams S.
      • et al.
      Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly.
      ,
      • Adams R.H.
      Molecular control of arterial-venous blood vessel identity.
      ,
      • Swift M.R.
      • Weinstein B.M.
      Arterial-venous specification during development.
      ]. Vein graft adaptation is characterized by loss of Eph-B4 expression, for example, loss of venous identity, but Ephrin-B2 is not expressed, for example, arterial identity is not gained [
      • Kudo F.A.
      • Muto A.
      • Maloney S.P.
      • et al.
      Venous identity is lost but arterial identity is not gained during vein graft adaptation.
      ]. However, similar characterization of the changes that occur during AVF maturation is not yet available. Downstream signaling in the Ephrin-Eph pathway may mediate many effects of venous remodeling, but the significance of this pathway as a potential source of therapeutic manipulation is not yet known. However, because Eph signaling is the upstream of the E2F pathway, modulation of the Eph pathway may provide therapeutic benefit, unlike the disappointing failure of the PREVENT trials [
      • Conte M.S.
      • Bandyk D.F.
      • Clowes A.W.
      • et al.
      Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery.
      ,
      • Conte M.S.
      Molecular engineering of vein bypass grafts.
      ].

      7.2 Endothelial signaling

      The venous endothelium releases mitogens and chemotactic agents, regulators of extracellular matrix remodeling, and vasoactive signals that regulate wall dilation to allow vessel adaptation to flow, shear stress, pressure, and tension (Fig. 2) [
      • Rothuizen T.C.
      • Wong C.
      • Quax P.H.
      • van Zonneveld A.J.
      • Rabelink T.J.
      • Rotmans J.I.
      Arteriovenous access failure: more than just intimal hyperplasia?.
      ]. Endothelial injury and denudation disrupt endothelial signaling leading to impaired adaptation. Flow-related endothelial denudation can occur within hours of AVF creation, and chronic kidney disease may delay re-endothelialization; denudation leads to barrier dysfunction, exposure of subendothelial collagen, thrombus formation, and inflammatory cell extravasation into the vein wall [
      • Liang A.
      • Wang Y.
      • Han G.
      • Truong L.
      • Cheng J.
      Chronic kidney disease accelerates endothelial barrier dysfunction in a mouse model of an arteriovenous fistula.
      ,
      • Manning E.
      • Skartsis N.
      • Orta A.M.
      • et al.
      A new arteriovenous fistula model to study the development of neointimal hyperplasia.
      ]. A similar process occurs in vein grafts, where endothelial denudation can occur within an hour after implantation [
      • Zwolak R.M.
      • Adams M.C.
      • Clowes A.W.
      Kinetics of vein graft hyperplasia: association with tangential stress.
      ,
      • Dilley R.J.
      • McGeachie J.K.
      • Prendergast F.J.
      A review of the histologic changes in vein-to-artery grafts, with particular reference to intimal hyperplasia.
      ]. Both the stress of the arterial environment and the surgical injury likely contribute to endothelial loss and dysfunction. The endothelium is regenerated 2 wk after both vein graft implantation and AVF creation, although endothelial proliferation continues for several weeks afterward [
      • Manning E.
      • Skartsis N.
      • Orta A.M.
      • et al.
      A new arteriovenous fistula model to study the development of neointimal hyperplasia.
      ,
      • Zwolak R.M.
      • Adams M.C.
      • Clowes A.W.
      Kinetics of vein graft hyperplasia: association with tangential stress.
      ].
      Figure thumbnail gr2
      Fig. 2Diagram depicting molecular pathways mediating venous adaptation to the arterial environment. iNOS = inducible nitric oxide synthase; TNF-α = tumor necrosis factor-α.
      In endothelial cells, nitric oxide (NO) is produced by endothelial nitric oxide synthase (eNOS) and is a potent vasodilator and signaling molecule with anti-inflammatory and anti-platelet properties [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Mitra A.K.
      • Gangahar D.M.
      • Agrawal D.K.
      Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia.
      ]. eNOS may contribute to adaptive vein wall remodeling both through its anti-inflammatory and anti-thrombotic properties and through its anti-proliferative properties [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ]. Both eNOS and inducible nitric oxide synthase are upregulated in the AVF and may mediate adaptation; inhibition of eNOS results in increased monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-8, leading to neointimal hyperplasia [
      • Caplice N.M.
      • Wang S.
      • Tracz M.
      • et al.
      Neoangiogenesis and the presence of progenitor cells in the venous limb of an arteriovenous fistula in the rat.
      ,
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ]. Similarly in vein grafts, NO limits neointimal thickening, cell proliferation, and macrophage infiltration [
      • Ohta S.
      • Komori K.
      • Yonemitsu Y.
      • Onohara T.
      • Matsumoto T.
      • Sugimachi K.
      Intraluminal gene transfer of endothelial cell-nitric oxide synthase suppresses intimal hyperplasia of vein grafts in cholesterol-fed rabbit: a limited biological effect as a result of the loss of medial smooth muscle cells.
      ,
      • Wu J.
      • Wadsworth R.M.
      • Kennedy S.
      Inhibition of inducible nitric oxide synthase promotes vein graft neoadventitial inflammation and remodelling.
      ], whereas inducible nitric oxide synthase may inhibit intimal and adventitial thickening [
      • Wu J.
      • Wadsworth R.M.
      • Kennedy S.
      Inhibition of inducible nitric oxide synthase promotes vein graft neoadventitial inflammation and remodelling.
      ,
      • Meng Q.H.
      • Irvine S.
      • Tagalakis A.D.
      • McAnulty R.J.
      • McEwan J.R.
      • Hart S.L.
      Inhibition of neointimal hyperplasia in a rabbit vein graft model following non-viral transfection with human iNOS cDNA.
      ].
      Endothelin-1 (ET-1) is an inflammatory mediator of vasoconstriction and endothelial proliferation. ET-1 expression is upregulated in the venous wall and within areas of neointimal hyperplasia in AVF and in the plasma of patients with chronic renal failure and hemodialysis. ET-1 may mediate wall thickening in response to localized hemodynamic forces [
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Weiss M.F.
      • Scivittaro V.
      • Anderson J.M.
      Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.
      ,
      • Jones G.T.
      • van Rij A.M.
      • Packer S.G.
      • Walker R.J.
      • Stehbens W.E.
      Venous endothelial changes in therapeutic arteriovenous fistulae.
      ]. Similarly in vein grafts, high densities of ET-1 receptors are present within subintimal regions that coincide with areas of proliferating cells. In a pig vein graft model, treatment with an ET-1 receptor antagonist resulted in decreased cell proliferation, decreased intimal and medial vein graft thickening, and increased luminal dilation [
      • Jeremy J.Y.
      • Shukla N.
      • Angelini G.D.
      • Wan S.
      Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists.
      ,
      • Wan S.
      • Yim A.P.
      • Johnson J.L.
      • et al.
      The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts.
      ].
      The opposing roles played by ET-1 and NOS are balanced by the venous endothelium during vein graft adaptation; however, arterial stress-induced endothelial injury and denudation disrupts this balance and likely is a mechanism of impaired venous adaptation. This pathway may be fruitful for consideration of modulation in future clinical studies. However, differences between arterial and venous ET-1 function suggest that results derived from arterial models may need to be interpreted cautiously in the context of venous remodeling [
      • Mitra A.K.
      • Gangahar D.M.
      • Agrawal D.K.
      Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia.
      ].

      7.3 Inflammatory and coagulation pathways

      Numerous inflammatory mediators are present during venous remodeling. In an AVF, inflammatory cells accumulate rapidly, with additional accumulation in segments that thrombose [
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ,
      • Chang C.J.
      • Ko Y.S.
      • Ko P.J.
      • et al.
      Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity.
      ,
      • Pascarella L.
      • Lulic D.
      • Penn A.H.
      • et al.
      Mechanisms in experimental venous valve failure and their modification by Daflon 500 mg.
      ]. IL-6, IL-8, MCP-1, and plasminogen activator inhibitor-1 (PAI-1) expressions are upregulated in the AVF, and these mediators are associated with fistula failure [
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ,
      • De Marchi S.
      • Falleti E.
      • Giacomello R.
      • et al.
      Risk factors for vascular disease and arteriovenous fistula dysfunction in hemodialysis patients.
      ]. IL-6 and tumor necrosis factor-α are more highly expressed in thrombosed AVF, and both C-reactive protein (CRP) and fibrinogen are associated with AVF failure [
      • Chang C.J.
      • Ko Y.S.
      • Ko P.J.
      • et al.
      Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity.
      ,
      • Kaygin M.A.
      • Halici U.
      • Aydin A.
      • et al.
      The relationship between arteriovenous fistula success and inflammation.
      ].
      The anti-inflammatory molecule heme oxygenase-1 (HO-1), an inducible stress protein involved in heme metabolism, regulates ECM deposition, endothelial proliferation, oxidative stress, and smooth muscle proliferation. HO-1 expression is upregulated within AVF and reduced HO-1 activity is associated with AVF failure [
      • Caplice N.M.
      • Wang S.
      • Tracz M.
      • et al.
      Neoangiogenesis and the presence of progenitor cells in the venous limb of an arteriovenous fistula in the rat.
      ,
      • Tsapenko M.V.
      • d'Uscio L.V.
      • Grande J.P.
      • et al.
      Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula.
      ,
      • Lin C.C.
      • Yang W.C.
      • Lin S.J.
      • et al.
      Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients.
      ]. HO-1 knockout mice develop increased neointimal hyperplasia and decreased AVF patency, with corresponding increased expression of PAI-1, MCP-1, matrix metalloproteinase (MMP)-2, and MMP-9 [
      • Tsapenko M.V.
      • d'Uscio L.V.
      • Grande J.P.
      • et al.
      Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula.
      ,
      • Juncos J.P.
      • Tracz M.J.
      • Croatt A.J.
      • et al.
      Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse.
      ].
      Inflammatory cells such as macrophages and granulocytes are recruited to vein grafts rapidly after implantation and are associated with expression of both proinflammatory and anti-inflammatory mediators; increased expression of inflammatory mediators may result in negative wall remodeling and intimal hyperplasia [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • Faries P.L.
      • Marin M.L.
      • Veith F.J.
      • et al.
      Immunolocalization and temporal distribution of cytokine expression during the development of vein graft intimal hyperplasia in an experimental model.
      ,
      • Nguyen B.T.
      • Yu P.
      • Tao M.
      • Hao S.
      • Jiang T.
      • Ozaki C.K.
      Perivascular innate immune events modulate early murine vein graft adaptations.
      ,
      • Sharony R.
      • Pintucci G.
      • Saunders P.C.
      • et al.
      Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2.
      ]. Interestingly, there is significantly higher induction of the proinflammatory IL-1β and less induction of the anti-inflammatory IL-10 within low flow vein grafts that correlates with increased intimal hyperplasia [
      • Jiang Z.
      • Berceli S.A.
      • Pfahnl C.L.
      • et al.
      Wall shear modulation of cytokines in early vein grafts.
      ]. Elevated high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, is associated with impaired positive remodeling, increased wall stiffness, suggesting an increased risk of failure in vein grafts [
      • Owens C.D.
      • Rybicki F.J.
      • Wake N.
      • et al.
      Early remodeling of lower extremity vein grafts: inflammation influences biomechanical adaptation.
      ]. Failing vein grafts are also associated with increased levels of PAI-1 and diminished tissue plasminogen activator (tPA) [
      • Kauhanen P.
      • Siren V.
      • Carpen O.
      • Vaheri A.
      • Lepantalo M.
      • Lassila R.
      Plasminogen activator inhibitor-1 in neointima of vein grafts: its role in reduced fibrinolytic potential and graft failure.
      ]. Similar to the data reported for AVF, HO-1 is also protective against vein graft failure, as vein grafts derived from HO-1 knockout mice demonstrate enhanced neointima compared with veins from wild-type mice [
      • Yet S.F.
      • Layne M.D.
      • Liu X.
      • et al.
      Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling.
      ]. Finally, a variety of anti-inflammatory agents decrease vein graft neointimal proliferation in animal models [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ].

      7.4 Reactive oxygen species

      Oxidative stress and injury stimulates synthesis and secretion of reactive oxygen species (ROS) that in turn regulate numerous signaling pathways, regulating diverse processes such as smooth muscle cell migration and proliferation, and activate latent MMP, potentially mediating many aspects of venous remodeling [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • Anwar M.A.
      • Shalhoub J.
      • Lim C.S.
      • Gohel M.S.
      • Davies A.H.
      The effect of pressure-induced mechanical stretch on vascular wall differential gene expression.
      ,
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Weiss M.F.
      • Scivittaro V.
      • Anderson J.M.
      Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.
      ]. For example, superoxide can deplete NO, resulting in disruption of numerous pathways [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • West N.
      • Guzik T.
      • Black E.
      • Channon K.
      Enhanced superoxide production in experimental venous bypass graft intimal hyperplasia: role of NAD(P)H oxidase.
      ].
      Oxidative stress is associated with end-stage renal disease and dialysis and, therefore, is likely to be present at all times an AVF is present [
      • Weiss M.F.
      • Scivittaro V.
      • Anderson J.M.
      Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.
      ]. In the artery proximal to an AVF, ROS mediate arterial flow–dependent remodeling via MMP activation [
      • Castier Y.
      • Brandes R.P.
      • Leseche G.
      • Tedgui A.
      • Lehoux S.
      p47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling.
      ]. In the venous limb of the AVF markers and products of oxidative stress are elevated in neointimal lesions, often colocalizing with the cytokines of growth and proliferation [
      • Weiss M.F.
      • Scivittaro V.
      • Anderson J.M.
      Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.
      ]. AVF demonstrate increased superoxide and decreased superoxide dismutase coordinately with induction of HO-1; addition of a superoxide scavenger decreases venous neointimal thickening and calcification within the AVF [
      • Tsapenko M.V.
      • d'Uscio L.V.
      • Grande J.P.
      • et al.
      Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula.
      ].
      With increased surgical manipulation, including removal from the surrounding tissues and disruption of vasa vasorum, vein grafts are associated with oxidative stress as well as ischemia-reperfusion injury that lead to generation of ROS [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • Hagen P.O.
      • Davies M.G.
      • Schuman R.W.
      • Murray J.J.
      Reduction of vein graft intimal hyperplasia by ex vivo treatment with desferrioxamine manganese.
      ]. Superoxide is produced in vein grafts and released from intimal smooth muscle cells, mediated by NAD(P)H oxidase [
      • West N.
      • Guzik T.
      • Black E.
      • Channon K.
      Enhanced superoxide production in experimental venous bypass graft intimal hyperplasia: role of NAD(P)H oxidase.
      ]. Superoxide is reciprocally related to NO function, as decreased intimal hyperplasia is associated with decreased superoxide production and increased NO-mediated vein graft relaxation [
      • Hattori K.
      • Yamanouchi D.
      • Banno H.
      • et al.
      Celiprolol reduces the intimal thickening of autogenous vein grafts via an enhancement of nitric oxide function through an inhibition of superoxide production.
      ,
      • Kodama A.
      • Komori K.
      • Hattori K.
      • Yamanouchi D.
      • Kajikuri J.
      • Itoh T.
      Sarpogrelate hydrochloride reduced intimal hyperplasia in experimental rabbit vein graft.
      ]. A variety of free radical scavengers such as desferoxamine manganese and superoxide dismutase reduce intimal hyperplasia in vein graft models [
      • Hagen P.O.
      • Davies M.G.
      • Schuman R.W.
      • Murray J.J.
      Reduction of vein graft intimal hyperplasia by ex vivo treatment with desferrioxamine manganese.
      ,
      • Huynh T.T.
      • Davies M.G.
      • Trovato M.J.
      • Barber L.
      • Safi H.J.
      • Hagen P.O.
      Reduction of lipid peroxidation with intraoperative superoxide dismutase treatment decreases intimal hyperplasia in experimental vein grafts.
      ].

      7.5 Extracellular matrix

      Venous adaptation depends on coordinate synthesis, secretion, and degradation of ECM. The MMP family regulate ECM remodeling and allow cell migration through degradation of collagen and elastin and is stimulated by a variety of factors present during vein graft adaptation including flow, stretch, mechanical injury, inflammation, and oxidative stress [
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Chan C.Y.
      • Chen Y.S.
      • Ma M.C.
      • Chen C.F.
      Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats.
      ,
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ,
      • Misra S.
      • Fu A.A.
      • Anderson J.L.
      • et al.
      The rat femoral arteriovenous fistula model: increased expression of matrix metalloproteinase-2 and -9 at the venous stenosis.
      ,
      • Juncos J.P.
      • Tracz M.J.
      • Croatt A.J.
      • et al.
      Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse.
      ,
      • Lee E.S.
      • Shen Q.
      • Pitts R.L.
      • et al.
      Serum metalloproteinases MMP-2, MMP-9, and metalloproteinase tissue inhibitors in patients are associated with arteriovenous fistula maturation.
      ,
      • Southgate K.M.
      • Mehta D.
      • Izzat M.B.
      • Newby A.C.
      • Angelini G.D.
      Increased secretion of basement membrane-degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts.
      ]. In AVF, MMP-2 and MMP-9 expressions are upregulated, and a high serum ratio of MMP-2 to tissue inhibitor of metalloproteinases (TIMP) predicts AVF maturation [
      • Chan C.Y.
      • Chen Y.S.
      • Ma M.C.
      • Chen C.F.
      Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats.
      ,
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ,
      • Misra S.
      • Fu A.A.
      • Anderson J.L.
      • et al.
      The rat femoral arteriovenous fistula model: increased expression of matrix metalloproteinase-2 and -9 at the venous stenosis.
      ,
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ,
      • Pascarella L.
      • Lulic D.
      • Penn A.H.
      • et al.
      Mechanisms in experimental venous valve failure and their modification by Daflon 500 mg.
      ,
      • Lee E.S.
      • Shen Q.
      • Pitts R.L.
      • et al.
      Serum metalloproteinases MMP-2, MMP-9, and metalloproteinase tissue inhibitors in patients are associated with arteriovenous fistula maturation.
      ]. However, MMP-2 and MMP-9 are also elevated in AVF stenoses and may play a role in thrombosis [
      • Misra S.
      • Fu A.A.
      • Anderson J.L.
      • et al.
      The rat femoral arteriovenous fistula model: increased expression of matrix metalloproteinase-2 and -9 at the venous stenosis.
      ,
      • Chang C.J.
      • Ko Y.S.
      • Ko P.J.
      • et al.
      Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity.
      ,
      • Juncos J.P.
      • Tracz M.J.
      • Croatt A.J.
      • et al.
      Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse.
      ,
      • Lee E.S.
      • Shen Q.
      • Pitts R.L.
      • et al.
      Serum metalloproteinases MMP-2, MMP-9, and metalloproteinase tissue inhibitors in patients are associated with arteriovenous fistula maturation.
      ]. Decreased expressions of MMP-1, MMP-3, and MMP-9 have been linked to increased AVF failure and stenosis that may be due to accumulation of ECM and impaired wall remodeling [
      • Lin C.C.
      • Yang W.C.
      • Chung M.Y.
      • Lee P.C.
      Functional polymorphisms in matrix metalloproteinases-1, -3, -9 are associated with arteriovenous fistula patency in hemodialysis patients.
      ]. The role of the TIMPs is not consistent and thus difficult to assess [
      • Chan C.Y.
      • Chen Y.S.
      • Ma M.C.
      • Chen C.F.
      Remodeling of experimental arteriovenous fistula with increased matrix metalloproteinase expression in rats.
      ,
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ,
      • Misra S.
      • Fu A.A.
      • Anderson J.L.
      • et al.
      The rat femoral arteriovenous fistula model: increased expression of matrix metalloproteinase-2 and -9 at the venous stenosis.
      ,
      • Misra S.
      • Shergill U.
      • Yang B.
      • Janardhanan R.
      • Misra K.D.
      Increased expression of HIF-1alpha, VEGF-A and its receptors, MMP-2, TIMP-1, and ADAMTS-1 at the venous stenosis of arteriovenous fistula in a mouse model with renal insufficiency.
      ]. Other elastases such as cathepsin S and cathepsin K are also upregulated in the AVF and may be associated with degradation of the internal elastic lamina [
      • Chang C.J.
      • Chen C.C.
      • Hsu L.A.
      • et al.
      Degradation of the internal elastic laminae in vein grafts of rats with aortocaval fistulae: potential impact on graft vasculopathy.
      ].
      In vein grafts, ECM deposition is likely to be the major mechanism of adaptation after 4 wk [
      • Westerband A.
      • Crouse D.
      • Richter L.C.
      • et al.
      Vein adaptation to arterialization in an experimental model.
      ,
      • Zwolak R.M.
      • Adams M.C.
      • Clowes A.W.
      Kinetics of vein graft hyperplasia: association with tangential stress.
      ,
      • Jiang Z.
      • Tao M.
      • Omalley K.A.
      • Wang D.
      • Ozaki C.K.
      • Berceli S.A.
      Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis.
      ]. Both MMP-2 and MMP-9 expressions are upregulated in the early developing neointima of vein grafts but decline to baseline between 3 and 6 mo, suggesting their role in early remodeling and cell migration [
      • Sharony R.
      • Pintucci G.
      • Saunders P.C.
      • et al.
      Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2.
      ,
      • Southgate K.M.
      • Mehta D.
      • Izzat M.B.
      • Newby A.C.
      • Angelini G.D.
      Increased secretion of basement membrane-degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts.
      ,
      • Jiang Z.
      • Tao M.
      • Omalley K.A.
      • Wang D.
      • Ozaki C.K.
      • Berceli S.A.
      Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis.
      ]. Interestingly, surgical preparation of vein grafts, including harvest, adventitial removal, distention, exposure to cold temperature, and so forth, activates MMP-2 and MMP-9 and coincides with partial endothelial denudation [
      • George S.J.
      • Zaltsman A.B.
      • Newby A.C.
      Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein.
      ]. Upregulation of Membrane type 1-MMP (MT1-MMP) (MMP-14), an activator of MMP-2, also occurs after vein graft implantation [
      • Sharony R.
      • Pintucci G.
      • Saunders P.C.
      • et al.
      Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2.
      ]. Elastase is also upregulated in vein grafts, and expression of an elastase inhibitor, elafin, protects against vein graft neointimal hyperplasia and inflammation within the venous wall [
      • O'Blenes S.B.
      • Zaidi S.H.
      • Cheah A.Y.
      • McIntyre B.
      • Kaneda Y.
      • Rabinovitch M.
      Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration.
      ]. TIMP-2 is downregulated early during vein graft adaptation, followed by a return to normal levels [
      • Sharony R.
      • Pintucci G.
      • Saunders P.C.
      • et al.
      Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2.
      ]. TIMP-1, however, increases in vein grafts [
      • Sun D.X.
      • Liu Z.
      • Tan X.D.
      • Cui D.X.
      • Wang B.S.
      • Dai X.W.
      Nanoparticle-mediated local delivery of an antisense TGF-beta1 construct inhibits intimal hyperplasia in autogenous vein grafts in rats.
      ]. Overexpression of TIMP-3 leads to decreased vein graft thickening [
      • George S.J.
      • Wan S.
      • Hu J.
      • MacDonald R.
      • Johnson J.L.
      • Baker A.H.
      Sustained reduction of vein graft neointima formation by ex vivo TIMP-3 gene therapy.
      ].
      Matrix degradation is regulated by MMP, whereas matrix deposition is regulated by transforming growth factor-β (TGF-β) that is produced by a variety of cell types, including endothelial, smooth muscle, and inflammatory cells, potentially contributing significantly to intimal and medial thickening [
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Heine G.H.
      • Ulrich C.
      • Sester U.
      • Sester M.
      • Kohler H.
      • Girndt M.
      Transforming growth factor beta1 genotype polymorphisms determine AV fistula patency in hemodialysis patients.
      ,
      • Wolff R.A.
      • Ryomoto M.
      • Stark V.E.
      • et al.
      Antisense to transforming growth factor-beta1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1.
      ]. TGF-β is upregulated at both early and later time points after AVF formation, depending on the model, and this expression correlates with ECM accumulation; TGF-β is also expressed within stenotic AVF and correlates with areas of ECM deposition [
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ,
      • Juncos J.P.
      • Tracz M.J.
      • Croatt A.J.
      • et al.
      Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse.
      ,
      • Ikegaya N.
      • Yamamoto T.
      • Takeshita A.
      • et al.
      Elevated erythropoietin receptor and transforming growth factor-beta1 expression in stenotic arteriovenous fistulae used for hemodialysis.
      ,
      • Stracke S.
      • Konner K.
      • Kostlin I.
      • et al.
      Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas.
      ]. Higher expression of TGF-β is associated with decreased AVF patency, likely due to increased deposition of ECM [
      • Heine G.H.
      • Ulrich C.
      • Sester U.
      • Sester M.
      • Kohler H.
      • Girndt M.
      Transforming growth factor beta1 genotype polymorphisms determine AV fistula patency in hemodialysis patients.
      ].
      TGF-β is similarly a potent stimulator of ECM deposition during early stages of vein graft adaptation [
      • Wolff R.A.
      • Ryomoto M.
      • Stark V.E.
      • et al.
      Antisense to transforming growth factor-beta1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1.
      ]. TGF-β1 messenger RNA (mRNA) expression is upregulated after vein graft implantation, whereas inhibition of TGF-β1 expression decreases neointimal hyperplasia and MCP-1 expression [
      • Sun D.X.
      • Liu Z.
      • Tan X.D.
      • Cui D.X.
      • Wang B.S.
      • Dai X.W.
      Nanoparticle-mediated local delivery of an antisense TGF-beta1 construct inhibits intimal hyperplasia in autogenous vein grafts in rats.
      ,
      • Wolff R.A.
      • Ryomoto M.
      • Stark V.E.
      • et al.
      Antisense to transforming growth factor-beta1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1.
      ]. Upregulation of TGF-β mRNA expression in vein grafts is associated with increased expression of collagen I and collagen III mRNA [
      • You W.J.
      • Xiao M.D.
      • Yuan Z.X.
      Significance of changes in transforming growth factor-beta mRNA levels in autogenous vein grafts.
      ]. Both TGF-β and connective tissue growth factor expression are upregulated in vein graft neointima despite diminished neointima cellularity [
      • Jiang Z.
      • Tao M.
      • Omalley K.A.
      • Wang D.
      • Ozaki C.K.
      • Berceli S.A.
      Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis.
      ].

      7.6 Growth factors and cell adhesion molecules

      Numerous growth factors and cytokines play a role during venous adaptation, both through pathways that control ECM synthesis, secretion, and degradation and through the control of cell proliferation and migration. For example, insulin-like growth factor-1 (IGF-1) induces ECM synthesis, smooth muscle proliferation and migration, and inhibits apoptosis in AVF [
      • Stracke S.
      • Konner K.
      • Kostlin I.
      • et al.
      Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas.
      ]. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) also play significant roles in stimulating cell proliferation and migration [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ]. Both PDGF-α/β and IGF-1 expressions are upregulated in AVF [
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ,
      • Juncos J.P.
      • Tracz M.J.
      • Croatt A.J.
      • et al.
      Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse.
      ]. Vascular endothelial growth factor (VEGF) plays several roles in vascular remodeling, including stimulation of endothelial proliferation and differentiation, modulation of smooth muscle cell proliferation and migration, angiogenesis, and modulation of the inflammatory response [
      • Zhang J.
      • Silva T.
      • Yarovinsky T.
      • et al.
      VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling.
      ,
      • Yang B.
      • Janardhanan R.
      • Vohra P.
      • et al.
      Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation.
      ,
      • Jadlowiec C.C.
      • Feigel A.
      • Yang C.
      • et al.
      Reduced adult endothelial cell EphB4 function promotes venous remodeling.
      ]. Interestingly, VEGF may play an inhibitory role in AVF adaptation because inhibition of VEGF-A is associated with increased lumen area and decreased inward remodeling [
      • Yang B.
      • Janardhanan R.
      • Vohra P.
      • et al.
      Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation.
      ].
      Similarly in vein grafts, PDGF and bFGF expressions are upregulated and correlate with intimal thickening [
      • Faries P.L.
      • Marin M.L.
      • Veith F.J.
      • et al.
      Immunolocalization and temporal distribution of cytokine expression during the development of vein graft intimal hyperplasia in an experimental model.
      ]. Inhibitors of the PDGF receptor and bFGF inhibit smooth muscle cell migration and proliferation leading to diminished neointimal hyperplasia [
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Hu Y.
      • Zou Y.
      • Dietrich H.
      • Wick G.
      • Xu Q.
      Inhibition of neointima hyperplasia of mouse vein grafts by locally applied suramin.
      ]. IGF-1 receptor expression is upregulated by mechanical stretch and deletion of the IGF-1 receptor leads to diminished neointimal hyperplasia in vein grafts [
      • Cheng J.
      • Du J.
      Mechanical stretch simulates proliferation of venous smooth muscle cells through activation of the insulin-like growth factor-1 receptor.
      ]. VEGF expression is upregulated during vein graft implantation and is a negative regulator of intimal hyperplasia; inhibition of VEGF activity increases thickness of the vein graft intima-media [
      • Westerband A.
      • Crouse D.
      • Richter L.C.
      • et al.
      Vein adaptation to arterialization in an experimental model.
      ,
      • Kudo F.A.
      • Muto A.
      • Maloney S.P.
      • et al.
      Venous identity is lost but arterial identity is not gained during vein graft adaptation.
      ]. Interestingly, the effects of VEGF-A during vein graft adaptation may be mediated by the Eph signaling pathway [
      • Kudo F.A.
      • Muto A.
      • Maloney S.P.
      • et al.
      Venous identity is lost but arterial identity is not gained during vein graft adaptation.
      ]. Conversely, incubation of vein grafts in VEGF decreases intimal thickening [
      • Luo Z.
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      • Tsurumi Y.
      • Isner J.M.
      • Symes J.F.
      Reduction of vein graft intimal hyperplasia and preservation of endothelium-dependent relaxation by topical vascular endothelial growth factor.
      ].
      MCP-1 regulates chemotaxis, endothelial activation, and stimulation of smooth muscle proliferation and migration, and plasma MCP-1 levels are increased in patients with kidney disease. [
      • Juncos J.P.
      • Grande J.P.
      • Kang L.
      • et al.
      MCP-1 contributes to arteriovenous fistula failure.
      ,
      • Stark V.K.
      • Hoch J.R.
      • Warner T.F.
      • Hullett D.A.
      Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia.
      ]. MCP-1 is increased in AVF and reduced MCP-1 activity is associated with increased AVF patency, increased luminal area and decreased wall thickness [
      • Juncos J.P.
      • Grande J.P.
      • Kang L.
      • et al.
      MCP-1 contributes to arteriovenous fistula failure.
      ,
      • Nath K.A.
      • Kanakiriya S.K.
      • Grande J.P.
      • Croatt A.J.
      • Katusic Z.S.
      Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.
      ,
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ]. Increased serum MCP-1 is also associated with AVF failure [
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      • Giacomello R.
      • et al.
      Risk factors for vascular disease and arteriovenous fistula dysfunction in hemodialysis patients.
      ]. In vein grafts, MCP-1 expression is increased immediately after implantation and remains elevated for several weeks [
      • Stark V.K.
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      • Warner T.F.
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      Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia.
      ]. Treatment of vein grafts with an antagonist to the MCP-1 receptor CCR2 diminished thickening [
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      ].
      Selectins facilitate leukocyte adhesion. P-selectin is present on endothelial cells and platelets, and E-selectin is present on endothelial cells; intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) facilitate additional binding and migration [
      • Shuhaiber J.H.
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      ]. P-selectin and E-selectin expressions are both upregulated early after AVF creation, followed by decreased P-selectin expression after 1 mo [
      • Croatt A.J.
      • Grande J.P.
      • Hernandez M.C.
      • Ackerman A.W.
      • Katusic Z.S.
      • Nath K.A.
      Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
      ]. VCAM-1, but not ICAM-1, is highly expressed in thrombosed and stenotic AVF [
      • Chang C.J.
      • Ko Y.S.
      • Ko P.J.
      • et al.
      Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity.
      ]. β-catenin and c-Myc expressions are increased 1 wk after AVF creation, correlating with decreased N-cadherin and associated with smooth muscle cell proliferation [
      • Nath K.A.
      • Grande J.P.
      • Kang L.
      • et al.
      β-Catenin is markedly induced in a murine model of an arteriovenous fistula: the effect of metalloproteinase inhibition.
      ]. In vein grafts, ICAM-1 expression is increased soon after implantation, and vein grafts derived from ICAM knockout mice have fewer adherent macrophages and 30%–50% less neointimal hyperplasia [
      • Zou Y.
      • Hu Y.
      • Mayr M.
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      Reduced neointima hyperplasia of vein bypass grafts in intercellular adhesion molecule-1-deficient mice.
      ].

      8. Failure of venous remodeling

      Despite the ability of vein grafts and AVF to remodel and adapt successfully to the arterial environment, vein grafts and AVF still exhibit significant rates of failure. AVF show two distinct phases of failure; AVF failure can occur early due to lack of sufficient maturation, as well as failure later, after successful maturation, due to neointimal hyperplasia that may result in stenosis or thrombosis. Vein grafts show similar patterns of early and later failure. We believe that despite somewhat different mechanisms of vein graft and AVF remodeling to the arterial environment, failure of successful remodeling leads to the early phase of clinical failure in both cases; similarly, later failure is generally associated with progression of disease in both cases as well. However, it is still not known whether the mechanisms that regulate successful venous remodeling become dysregulated and lead to later conduit failure. Therapeutic approaches to prevent failure include both cell-based therapies and gene therapy targeting many of the molecular pathways addressed in this article. Although a detailed review of these approaches is beyond the scope of this article, several excellent reviews have addressed this topic in detail [
      • Wan S.
      • George S.J.
      • Berry C.
      • Baker A.H.
      Vein graft failure: current clinical practice and potential for gene therapeutics.
      ,
      • Roy-Chaudhury P.
      • Spergel L.M.
      • Besarab A.
      • Asif A.
      • Ravani P.
      Biology of arteriovenous fistula failure.
      ,
      • Muto A.
      • Model L.
      • Ziegler K.
      • Eghbalieh S.D.
      • Dardik A.
      Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.
      ,
      • Collins M.J.
      • Li X.
      • Lv W.
      • et al.
      Therapeutic strategies to combat neointimal hyperplasia in vascular grafts.
      ,
      • Dixon B.S.
      Why don't fistulas mature?.
      ,
      • Lee T.
      • Roy-Chaudhury P.
      Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.
      ,
      • Conte M.S.
      Molecular engineering of vein bypass grafts.
      ,
      • Rothuizen T.C.
      • Wong C.
      • Quax P.H.
      • van Zonneveld A.J.
      • Rabelink T.J.
      • Rotmans J.I.
      Arteriovenous access failure: more than just intimal hyperplasia?.
      ].

      9. Conclusions

      The molecular mechanisms leading to cell proliferation and migration, and ECM synthesis, secretion, and degradation, are remarkably similar during vein graft and AVF adaptation to the arterial environment. Despite differences in vein graft adaptation, characterized mainly by wall thickening, and AVF maturation, characterized mainly by outward remodeling, the lack of identifiable molecular differences between these two processes remains a gap in our understanding of venous remodeling. Research directed toward understanding the effects of different hemodynamic and other environmental forces on veins may identify molecular differences between vein graft adaptation and AVF maturation and may depend on understanding the fundamental biological differences between responses of arteries and veins to these stimuli. Additional areas of research include regulation of apoptosis, endothelial phenotype, and the role of endothelial progenitor cells in venous remodeling.

      Acknowledgment

      This work was supported by the National Institutes of Health R01-HL095498 (A.D.) and TL1-RR024137 grants (D.Y.L.), the Yale Department of Surgery Ohse award (K.Y. and C.D.P.), the Yale University Medical Student Research Fellowship (E.Y.C.), the Society of Vascular Surgery Student Research Fellowship (E.Y.C.), the Doris Duke Foundation Clinical Fellowship (D.J.W.), as well as with the resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT (K.Y. and A.D.).

      Disclosure

      The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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